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Volume 13
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Biomedicines, Volume 13, Issue 10 (October 2025) – 212 articles

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18 pages, 684 KB  
Article
Fabry Disease Screening in Patients with Idiopathic HCM or LVH: Data from the Multicentric Nationwide F-CHECK Study
by Raquel Machado, Inês Fortuna, Sílvia Sousa, Catarina Costa, João Calvão, Ana Filipa Amador, Patrícia Rodrigues, Dulce Brito, Marta Vilela, Natália António, Vanessa Lopes, Cristina Gavina, Ana Sofia Correia, Conceição Queirós, Alexandra Toste, Alexandra Sousa, Ricardo Fontes-Carvalho, André Lobo, Inês Silveira, Janete Quelhas-Santos and Elisabete Martinsadd Show full author list remove Hide full author list
Biomedicines 2025, 13(10), 2530; https://doi.org/10.3390/biomedicines13102530 - 16 Oct 2025
Abstract
Background/Objectives: Fabry disease (FD) is a rare X-linked disease caused by the deficient activity of the enzyme α-galactosidase A. Cardiac involvement is particularly critical, often determining the disease prognosis. Epidemiological data on FD in Portugal are limited and inconsistent, highlighting the need [...] Read more.
Background/Objectives: Fabry disease (FD) is a rare X-linked disease caused by the deficient activity of the enzyme α-galactosidase A. Cardiac involvement is particularly critical, often determining the disease prognosis. Epidemiological data on FD in Portugal are limited and inconsistent, highlighting the need for targeted screening. The F-CHECK study aimed to determine the prevalence of FD through the systematic screening of a Portuguese cohort of patients with unexplained cardiomyopathies. Methods: This multicenter observational study (NCT05409846) assessed the prevalence and clinical characteristics of FD in a Portuguese cohort (n = 409) of patients from 10 central hospitals who presented with unexplained cardiomyopathies, including idiopathic hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy, dilated-phase HCM, and dilated cardiomyopathy with late gadolinium enhancement in the inferolateral segment. Screening was performed using dried blood spot assays to measure α-galactosidase A activity and/or by GLA gene sequencing in whole-blood samples. Results: FD was diagnosed in 14 patients, corresponding to a prevalence of 3.4%. FD diagnosis was significantly associated with systemic manifestations such as acroparesthesias (p = 0.027) and angiokeratomas (p = 0.003), as well as an increased risk of prior arrhythmic events (p = 0.021) and cerebrovascular disease (p = 0.016). Most FD patients (57%) presented a non-founder mutation in the GLA gene; however, they were pathogenically relevant. Conclusions: The observed 3.4% prevalence highlights the importance of systematic FD screening among Portuguese patients with unexplained cardiomyopathy, extending beyond classic hypertrophic presentations to dilated forms. Specific clinical signs, electrocardiogram findings, and cardiac imaging features can serve as valuable indicators to guide targeted genetic testing for FD. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
18 pages, 812 KB  
Review
Sleep Apnea: The Slept-Upon Cardiovascular Risk Factor
by Adriana-Loredana Pintilie, Dragos Traian Marius Marcu, Andreea Zabara-Antal, Raluca-Ioana Arcana, Diana-Gabriela Iosep, Mihnea Miron, Carina-Adina Afloarei, Mihai-Lucian Zabara and Radu Crisan Dabija
Biomedicines 2025, 13(10), 2529; https://doi.org/10.3390/biomedicines13102529 - 16 Oct 2025
Abstract
Background: Obstructive sleep apnea (OSA) is prevalent and often underdiagnosed in cardiology. Worldwide, approximately 936 million adults aged 30–69 are affected by OSA, with the highest numbers in the USA, China, Brazil, and India. In cardiovascular clinics, OSA is found in about 40–80% [...] Read more.
Background: Obstructive sleep apnea (OSA) is prevalent and often underdiagnosed in cardiology. Worldwide, approximately 936 million adults aged 30–69 are affected by OSA, with the highest numbers in the USA, China, Brazil, and India. In cardiovascular clinics, OSA is found in about 40–80% of patients with hypertension, heart failure, coronary artery disease, atrial fibrillation, or stroke. Meta-analyses link OSA to nearly twice the risk of cardiovascular disease, stroke, and all-cause mortality. Continuous positive airway pressure (CPAP) therapy addresses the underlying mechanisms of OSA and enhances intermediate cardiovascular indicators. Materials and Methods: We conducted a narrative review using major medical search engines (PubMed, Embase, Cochrane) to examine recent statements, meta-analyses, large cohorts, and key trials. The review focused on the cardiovascular burden of sleep apnea and its pathophysiology—including arrhythmic, hemodynamic, vascular, and coagulation aspects—as well as the effects of CPAP on intermediate cardiovascular outcomes. We aimed to provide a synthesised overview of current cardiovascular evidence related to the burden and mechanisms of OSA, and to summarise the effects of continuous positive airway pressure (CPAP) on intermediate and clinical cardiovascular outcomes. Results: Intermittent hypoxia, sleep fragmentation, and major negative fluctuations in intrathoracic pressure create a clear pathway leading to adverse cardiovascular outcomes. This occurs through mechanisms like sympathetic activation, RAAS activation, endothelial dysfunction, oxidative stress, and inflammation, linking OSA to these health issues. Studies show that greater severity of OSA correlates with higher cardiovascular risk, including increased incidence and recurrence of AF, resistant hypertension, and new cases of heart failure. CPAP effectively lowers AHI and enhances nocturnal oxygen levels, as well as intermediate cardiovascular indicators such as blood pressure, sympathetic activity, and certain aspects of ventricular function, with clinical benefits most evident in adherent patients. Conclusions: OSA is a significant, modifiable risk factor for cardiovascular disease. Routine cardiovascular care should include targeted screening for OSA, especially in cases of resistant hypertension, atrial fibrillation, and heart failure, along with timely sleep testing and adherence-focused CPAP therapy, in addition to traditional risk-reduction methods. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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18 pages, 2307 KB  
Article
Interference-Free Measurement of Urinary Angiotensin-Converting Enzyme (ACE) Activity: Diagnostic and Therapeutic Monitoring Implications
by Attila Ádám Szabó, Enikő Edit Enyedi, Tamás Bence Pintér, Ivetta Siket Mányiné, Csongor Váradi, Emese Bányai, Attila Tóth, Zoltán Papp and Miklós Fagyas
Biomedicines 2025, 13(10), 2528; https://doi.org/10.3390/biomedicines13102528 - 16 Oct 2025
Abstract
Background/Objectives: Urinary angiotensin-converting enzyme (uACE) activity has long been regarded as a promising biomarker for kidney and cardiovascular diseases; however, its clinical applicability has been limited by the presence of endogenous urinary inhibitors and technically demanding assay protocols. We aimed to establish [...] Read more.
Background/Objectives: Urinary angiotensin-converting enzyme (uACE) activity has long been regarded as a promising biomarker for kidney and cardiovascular diseases; however, its clinical applicability has been limited by the presence of endogenous urinary inhibitors and technically demanding assay protocols. We aimed to establish a fast and reproducible method for measuring uACE activity to identify the inhibitory compounds responsible for previous assay failures and to define practical preanalytical conditions suitable for routine laboratory implementation. Methods: A fluorescence-based kinetic assay was optimized for urine samples. Endogenous inhibitors were isolated by membrane filtration and chemically characterized, while the effect of sample dilution was evaluated as a simplified alternative for eliminating inhibitory interference. We assessed the stability of ACE activity under various storage conditions to support reliable measurement. Results: Urea (IC50 = 1.18 M), uric acid (IC50 = 3.61 × 10−3 M), and urobilinogen (IC50 = 2.98 × 10−4 M) were identified as the principal reversible inhibitors, jointly accounting for up to 90% suppression of uACE activity. Their inhibitory effect was effectively eliminated by a 128-fold dilution. ACE activity remained stable for 24 h at 25 °C but was completely lost after freezing. A strong positive correlation between uACE activity and creatinine concentration (r = 0.76, p < 0.0001) justified normalization. ACE activity-to-creatinine ratio turned out to be significantly lower in ACE inhibitor-treated patients than in untreated controls (6.49 vs. 36.69 U/mol, p < 0.0001). Conclusions: Our findings demonstrate that accurate measurement of uACE activity is feasible using a rapid dilution-based protocol. The normalized ACE activity can serve as a practical biomarker for detecting pharmacological ACE inhibition and monitoring therapy adherence in cardiovascular care and may also provide insight into renal pathophysiology such as tubular injury or local RAAS-related processes. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition)
29 pages, 8298 KB  
Article
Novel Cross-Cancer Hub Genes in Doxorubicin Resistance Identified by Transcriptional Mapping
by Arseny D. Moralev, Oleg V. Markov, Marina A. Zenkova and Andrey V. Markov
Biomedicines 2025, 13(10), 2527; https://doi.org/10.3390/biomedicines13102527 - 16 Oct 2025
Abstract
Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its efficacy is often limited by cancer cell resistance. Although multiple DOX resistance mechanisms have been characterized, the global transcriptomic alterations underlying this phenomenon remain poorly understood. The aim of this work was [...] Read more.
Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its efficacy is often limited by cancer cell resistance. Although multiple DOX resistance mechanisms have been characterized, the global transcriptomic alterations underlying this phenomenon remain poorly understood. The aim of this work was to determine whether a common transcriptional response associated with DOX desensitization exists across tumor cells of different origins and to identify the core elements of this response. Methods: We performed an integrated bioinformatics analysis, including: analysis of independent transcriptomic datasets (comparing DOX-resistant neuroblastoma, breast, and cervical carcinoma cells to their DOX-sensitive counterparts), functional annotation of differentially expressed genes, reconstruction and topology analysis of gene networks, text mining, and survival analysis. The findings were validated through in vitro functional tests, RT-PCR, and analysis of the Cancer Therapeutics Response Portal and The Cancer Genome Atlas. Results: We showed that DOX resistance in cancer cells is associated with cytoskeletal reorganization, modulation of cell adhesion, cholesterol biosynthesis, and dysregulation of mTORC1, Wnt, and Gβγ signaling pathways. Network analysis identified a conserved regulome of 37 resistance-linked genes, with GJA1, SEH1L, TCF3, TUBA4A, and ZYX emerging as central hubs (mean degree: 8.7–19.7; mean fold change: 2.4–21.3). Experimental validation in DOX-resistant KB-8-5 cervical carcinoma cells and their sensitive counterparts (KB-3-1) confirmed enhanced cellular adhesion and reduced intracellular cholesterol levels associated with chemoresistance, supporting our in silico findings. A detailed follow-up analysis verified the upregulation of these hub genes in chemoresistant cells and their correlation with poor clinical outcomes across multiple cancer types. Conclusions: This integrative analysis identifies conserved transcriptomic signatures of DOX resistance and highlights hub genes GJA1, SEH1L, TCF3, TUBA4A, and ZYX with potential as predictive biomarkers and therapeutic targets. Targeting these pathways may help overcome chemoresistance and improve treatment outcomes in cancer patients. Full article
(This article belongs to the Special Issue Drug Resistance and Tumor Microenvironment in Human Cancers)
38 pages, 37304 KB  
Article
Intraepithelial Lymphocytes and LAIR1 Expression in Celiac Disease
by Joaquim Carreras, Giovanna Roncador, Rifat Hamoudi, Jose Antoni Bombi and Yohei Masugi
Biomedicines 2025, 13(10), 2526; https://doi.org/10.3390/biomedicines13102526 - 16 Oct 2025
Abstract
Background: Celiac disease (CD) is a gluten-sensitive immune-related enteropathy of the small intestine characterized by villus atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Objectives: To characterize the phenotype of IELs and immune cells of the lamina propria of small intestine [...] Read more.
Background: Celiac disease (CD) is a gluten-sensitive immune-related enteropathy of the small intestine characterized by villus atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Objectives: To characterize the phenotype of IELs and immune cells of the lamina propria of small intestine control using immuno-oncology and immune-phenotype markers and test the most relevant marker, an immune checkpoint co-inhibitory receptor, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), in CD. Methods: Immunohistochemical analysis of CD3 (CD3E), CD4, CD8, CD103 (ITGAE), Granzyme B (GZMB), TCR beta (β), TCR delta (δ), CD56 (NCAM), CD16 (FCGR3A), LAIR1 (CD305), PD-L1 (CD274), PD1 (CD279), BTLA (CD272), TOX2, HVEM (TNFRSF14), CD163, HLA-DP-DQ-DR, IL4I1, and FOXP3 was performed using histological analysis. Gene expression analysis was performed using an independent dataset to expand and confirm the findings. Results: IELs exhibited a cytotoxic T-cell phenotype and were CD3+, CD8+, CD103+, TCR beta+, and LAIR1+. The lamina propria (LP) was abundant in CD163+, HLA-DP-DQ-DR+, BTLA+, PD-L1+, CD103+, CD56+, and LAIR1+ cells corresponding to macrophages and T- and B-lymphocytes. In CD, IELs and part of the inflammatory cells of the lamina propria cells were LAIR1+. CD was characterized by higher quantity of LAIR1+ IELs and LP immune cells than the small intestine control (p = 0.004). Higher intestinal lesions evaluated by Marsh scoring were correlated with higher LAIR1 (p < 0.001). Gene expression analysis confirmed the overexpression of the LAIR1 pathway in CD and highlighted BTLA. At the protein level, BTLA overexpression was confirmed in CD. Finally, as a proof-of-concept AI analysis, a convolutional neural network classified LAIR1-stained image patches between the three diagnoses of small intestine control, CD, and reactive tonsils with high accuracy (99.6%). Conclusions: IELs exhibit a cytotoxic T-cell phenotype and were found to be CD3+, CD8+, CD103+, TCR beta+, and LAIR1+ in the small intestine control. Increased numbers of LAIR1+ IELs and lamina propria immune cells characterize CD. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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21 pages, 3443 KB  
Review
Artificial Intelligence in the Management of Infectious Diseases in Older Adults: Diagnostic, Prognostic, and Therapeutic Applications
by Antonio Pinto, Flavia Pennisi, Stefano Odelli, Emanuele De Ponti, Nicola Veronese, Carlo Signorelli, Vincenzo Baldo and Vincenza Gianfredi
Biomedicines 2025, 13(10), 2525; https://doi.org/10.3390/biomedicines13102525 - 16 Oct 2025
Abstract
Background: Older adults are highly vulnerable to infectious diseases due to immunosenescence, multimorbidity, and atypical presentations. Artificial intelligence (AI) offers promising opportunities to improve diagnosis, prognosis, treatment, and continuity of care in this population. This review summarizes current applications of AI in [...] Read more.
Background: Older adults are highly vulnerable to infectious diseases due to immunosenescence, multimorbidity, and atypical presentations. Artificial intelligence (AI) offers promising opportunities to improve diagnosis, prognosis, treatment, and continuity of care in this population. This review summarizes current applications of AI in the management of infections in older adults across diagnostic, prognostic, therapeutic, and preventive domains. Methods: We conducted a narrative review of peer-reviewed studies retrieved from PubMed, Scopus, and Web of Science, focusing on AI-based tools for infection diagnosis, risk prediction, antimicrobial stewardship, prevention of healthcare-associated infections, and post-discharge care in individuals aged ≥65 years. Results: AI models, including machine learning, deep learning, and natural language processing techniques, have demonstrated high performance in detecting infections such as sepsis, pneumonia, and healthcare-associated infections (Area Under the Curve AUC up to 0.98). Prognostic algorithms integrating frailty and functional status enhance the prediction of mortality, complications, and readmission. AI-driven clinical decision support systems contribute to optimized antimicrobial therapy and timely interventions, while remote monitoring and telemedicine applications support safer hospital-to-home transitions and reduced 30-day readmissions. However, the implementation of these technologies is limited by the underrepresentation of frail older adults in training datasets, lack of real-world validation in geriatric settings, and the insufficient explainability of many models. Additional barriers include system interoperability issues and variable digital infrastructure, particularly in long-term care and community settings. Conclusions: AI has strong potential to support predictive and personalized infection management in older adults. Future research should focus on developing geriatric-specific, interpretable models, improving system integration, and fostering interdisciplinary collaboration to ensure safe and equitable implementation. Full article
(This article belongs to the Special Issue Feature Reviews in Infection and Immunity)
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13 pages, 2021 KB  
Article
The Impact of Dry Eye Disease on Corneal Biomechanics Analyzed with Corneal Visualization Scheimpflug Technology
by Li-Wen Chiu, Ren-Wen Ho, Hun-Ju Yu, Po-Chiung Fang, I-Hui Yang and Ming-Tse Kuo
Biomedicines 2025, 13(10), 2524; https://doi.org/10.3390/biomedicines13102524 - 16 Oct 2025
Abstract
Background/Objectives: Dry eye disease (DED) is an ocular surface disease with unstable tear film hemeostasis that could influence the corneal biomechanics. The study aimed to elucidate the impact of dry eye severity on corneal biomechanics. Methods: This is a prospective cohort [...] Read more.
Background/Objectives: Dry eye disease (DED) is an ocular surface disease with unstable tear film hemeostasis that could influence the corneal biomechanics. The study aimed to elucidate the impact of dry eye severity on corneal biomechanics. Methods: This is a prospective cohort study that enrolled 72 participants with or without dry eye severity. All subjects received dry eye and corneal biomechanic assessment. Dry eye patients were divided into non-DED (>6 s) and DED (<6 s) groups based on the average non-invasive keratograph tear break-up time to compare their performance in corneal biomechanics. We further analyzed the correlation between the corneal biomechanic parameters and dry eye indexes for these patients. Results: In this study, 38 non-DED patients and 34 DED patients were enrolled for analysis. The two groups showed significant differences in first applanation (A1) deflection area (p = 0.002), A1 delta arc length (p = 0.024), second applanation (A2) deformation amplitude (p = 0.024), and whole eye movement [mm] (p = 0.021). Moreover, both A1 deflection area and A1 delta arc length revealed significantly correlated with tear meniscus height in DED patients. Conclusions: DED and its severity can affect corneal biomechanics. Tear volume on the ocular surface could be one of the important factors to influence corneal biomechanics. Full article
(This article belongs to the Special Issue Recent Research on Dry Eye)
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21 pages, 1245 KB  
Systematic Review
Sex Differences in the Prevalence of Chronic Pain in Mid-Life: A Systematic Review and Meta-Analysis
by Catherine Borra, Jessica Pawson, Nathalie Rich and Rebecca Hardy
Biomedicines 2025, 13(10), 2523; https://doi.org/10.3390/biomedicines13102523 - 16 Oct 2025
Abstract
Background/Objectives: Chronic pain (CP) affects more females than males, but it is unclear how differences present at mid-life, a period characterized by distinct changes which may exacerbate inequality. Methods: Using a search strategy combining MeSH terms and Boolean operators, we searched [...] Read more.
Background/Objectives: Chronic pain (CP) affects more females than males, but it is unclear how differences present at mid-life, a period characterized by distinct changes which may exacerbate inequality. Methods: Using a search strategy combining MeSH terms and Boolean operators, we searched MEDLINE, EMBASE, AMED, and PSYCHinfo for population-representative cohort or cross-sectional studies of CP prevalence. We conducted a systematic review of CP prevalence by sex and the difference in prevalence of CP between sexes at mid-life through narrative synthesis and random-effects meta-analysis. A sensitivity analysis assessed how sex differences varied by pain type, pain definition, and geographic region. Results: Eighteen eligible articles provided information on CP prevalence by sex and demonstrated variation according to pain type. All but three studies found a higher prevalence of CP in females than males. Based on a random-effects meta-analysis of eight studies, the overall relative risk (RR) was 1.16 (95% CI: 1.11–1.21) for females compared with males, with no evidence of heterogeneity. However, in subgroup analyses, the RR was lower for generic CP (RR = 1.16, 95% CI: 1.11–1.21) than for fibromyalgia (RR = 3.13, 95% CI: 1.22–8.04). Conclusions: Our review found that females are more likely to experience CP at mid-life, although the RR was small. Larger sex differences may be observed for fibromyalgia, but the small sample sizes highlight the need for larger studies to provide more precise estimates of different types of pain. Full article
(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies—Second Edition)
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12 pages, 273 KB  
Article
Effects of Antifibrotic Therapy in Patients with Combined Pulmonary Fibrosis and Emphysema: A US-Based Cohort Study
by Abhishek Shah, Esteban Kosak Lopez, Andrew Geller, Maanav Patel and Sadia Benzaquen
Biomedicines 2025, 13(10), 2522; https://doi.org/10.3390/biomedicines13102522 - 16 Oct 2025
Abstract
Background/Objectives: Combined pulmonary fibrosis and emphysema (CPFE) is associated with poor outcomes. We investigated the association of antifibrotic therapy on patients with CPFE. Methods: This retrospective study included adult patients, older than 18 years, with a diagnosis of CPFE between 2015 [...] Read more.
Background/Objectives: Combined pulmonary fibrosis and emphysema (CPFE) is associated with poor outcomes. We investigated the association of antifibrotic therapy on patients with CPFE. Methods: This retrospective study included adult patients, older than 18 years, with a diagnosis of CPFE between 2015 and 2019 using TrinetX database. CPFE was defined as a diagnosis of pulmonary fibrosis (PF) and emphysema or chronic obstructive pulmonary disease. Propensity score matching was performed to compare baseline characteristics for CPFE patients on antifibrotic therapy (nintendanib and pirfenidone) with those not on antifibrotic therapy. The outcomes studied included all-cause mortality, major adverse cardiac event (MACE, [myocardial infarction, unstable angina]), hypoxic and hypercapnic respiratory failure, and stroke. These outcomes were compared at one-, three-, and five-year follow-ups. Results: Patients were divided into two cohorts: those on antifibrotic therapy (cohort 1, n = 861) and those without antifibrotic therapy (cohort 2, n = 861). Although not statistically significant, there was a trend towards increased mortality in cohort 1 at the 5-year follow-up (HR 1.14; CI 0.99–1.33). There was also an increased incidence of MI (HR 1.68; CI 0.88–1.47) and hypoxic respiratory failure (HR 1.17; CI 0.99–1.39). Notably, there was also a trend towards decreased incidence of stroke (HR 0.73; CI 0.51–1.05), and no difference in unstable angina (HR 0.94; CI 0.47–1.86) and hypercapnic respiratory failure (HR 0.99; CI 0.67–1.47). Conclusions: For patients with CFPE, antifibrotic use demonstrated a trend towards increased risk of mortality at 5-year follow-up, raising concerns for “sicker patient” bias. Prospective studies should be designed to include patients with CPFE and evaluate the benefits of antifibrotics. Full article
(This article belongs to the Special Issue Navigating the Complex Landscape of Non-Communicable Respiratory Diseases: Emerging Challenges and Opportunities)
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29 pages, 2004 KB  
Review
Emerging Roles of Extracellular Vesicles in the Pathogenesis, Diagnosis, and Therapy of Periodontitis
by Yiru Fu, Mengmeng Wang, Rui Teng and Ang Li
Biomedicines 2025, 13(10), 2521; https://doi.org/10.3390/biomedicines13102521 - 16 Oct 2025
Abstract
Periodontitis is a globally prevalent oral disease and is closely associated with various systemic diseases. Periodontitis arises from dynamic and complex interactions between polymicrobial communities and host immune responses. Extracellular vesicles (EVs) are circulating subcellular particles carrying multiple signaling molecules. EVs play a [...] Read more.
Periodontitis is a globally prevalent oral disease and is closely associated with various systemic diseases. Periodontitis arises from dynamic and complex interactions between polymicrobial communities and host immune responses. Extracellular vesicles (EVs) are circulating subcellular particles carrying multiple signaling molecules. EVs play a key role in intercellular communication, and hold promise for diagnostic and therapeutic purposes. Bacterial extracellular vesicles (BEVs), released from oral pathogens, have been implicated in delivering virulence factors to host cells. In contrast, host cell-derived EVs (CEVs), secreted by periodontal cells, contain molecular cargo that reflect disease status. Both BEVs and CEVs contribute to periodontitis progression by exacerbating inflammation and tissue destruction, and they may also influence related systemic diseases. Moreover, the molecular components of EVs derived from saliva and gingival crevicular fluid (GCF) show potential as diagnostic biomarkers for periodontitis. In addition, mesenchymal stem cell-derived EVs (MSC-EVs) exhibit therapeutic potential in periodontitis, and engineering approaches have been developed to enhance their therapeutic efficacy and accelerate clinical translation. This review summarizes recent advances in understanding the pathogenic, diagnostic, and therapeutic roles of EVs in periodontitis and discusses current challenges and future directions toward their clinical application. Full article
(This article belongs to the Special Issue Biomedicine in Dental and Oral Rehabilitation)
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16 pages, 1463 KB  
Review
Macrophages in Autoimmune Liver Diseases: From Immune Homeostasis to Precision-Targeted Therapy
by Tianfu Liu, Yizhe Wang, Yichen Huang, Rui Zhao and Haili Shen
Biomedicines 2025, 13(10), 2520; https://doi.org/10.3390/biomedicines13102520 - 16 Oct 2025
Abstract
Autoimmune liver diseases (AILDs) represent a diverse spectrum of chronic inflammatory conditions characterized primarily by compromised hepatic immune tolerance, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Recent evidence positions macrophages as pivotal players in AILDs pathogenesis, attributable [...] Read more.
Autoimmune liver diseases (AILDs) represent a diverse spectrum of chronic inflammatory conditions characterized primarily by compromised hepatic immune tolerance, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Recent evidence positions macrophages as pivotal players in AILDs pathogenesis, attributable to their multifaceted roles in inflammation amplification, immune regulation, and fibrogenesis. In the context of AILDs, macrophages exhibit marked polarization imbalance, increased recruitment of monocytes, and impaired clearance of apoptotic cells. Through complex interactions with T lymphocytes and hepatic stellate cells, macrophages orchestrate a pathological milieu promoting inflammation and fibrosis. Notably, diverse programmed cell death (PCD) modalities—autophagy, necroptosis, pyroptosis, and ferroptosis—not only determine macrophage survival and functional phenotype but also significantly impact cytokine release, phenotypic plasticity, and the trajectory of immunopathological progression. This review synthesizes current understandings of macrophage-driven immunoregulatory mechanisms in AILDs, characterizes the regulatory attributes of various macrophage-related PCD processes, and evaluates their relevance in experimental disease models. Furthermore, we highlight recent advancements in biomarker identification and targeted therapeutic strategies. Comprehensive elucidation of the interplay between macrophage immunological activity and programmed cell death pathways promises to inform novel, personalized therapeutic approaches for patients with AILDs. Full article
(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)
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11 pages, 703 KB  
Article
Finerenone in Patients with Nondiabetic Chronic Kidney Disease—A Retrospective Study
by Rehab B. Albakr, Fadel AlRowaie, Ibrahim A. Sandokji, Yazid A. Alhadlg, Khalid Almatham and Abdulaziz B. Albacker
Biomedicines 2025, 13(10), 2519; https://doi.org/10.3390/biomedicines13102519 - 15 Oct 2025
Abstract
Background & Objectives: Data on the efficacy and adverse effects of finerenone in patients with nondiabetic chronic kidney disease (CKD) are limited, particularly regarding ethnic diversity. This study aimed to evaluate the outcomes of finerenone in patients with nondiabetic CKD previously treated with [...] Read more.
Background & Objectives: Data on the efficacy and adverse effects of finerenone in patients with nondiabetic chronic kidney disease (CKD) are limited, particularly regarding ethnic diversity. This study aimed to evaluate the outcomes of finerenone in patients with nondiabetic CKD previously treated with standard therapies and investigate associated adverse effects, including hyperkalemia and hypotension. Methods: This is a retrospective exploratory study. It is a single-center study including patients with nondiabetic CKD who visited King Fahad Medical City in Riyadh, Saudi Arabia. The primary exposure was finerenone treatment, assessing its effects on albuminuria, kidney function, and blood pressure (BP), following prior use of renin–angiotensin–aldosterone system and sodium–glucose transport protein 2 inhibitors. The measured outcomes were the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The UACR (primary endpoint) was calculated as the mean of two morning spot urine samples collected consecutively 1 day apart. During each 4-week treatment period, secondary endpoints included changes in UACR, as determined by a 24 h urine sample, BP, and eGFR. The Wilcoxon signed-rank test was used to compare changes in continuous variables before and after therapy initiation. Statistical significance was set at p < 0.05. Results: This study included 16 patients with nondiabetic CKD (median age, 38.5 years [range, 35–50 years]; 56.3% male). The baseline eGFR was 66 mL/min/1.73 m2 (47–82.5), with a UACR of 90.0 mg/g (58.8–132.5). No hyperkalemia was observed (potassium level, 4 mmol/L [3.8–4.4]). However, significant reductions in systolic and diastolic BPs were observed. Albuminuria improved significantly: the UACR decreased from 90.0 to 39.3 mg/g (p = 0.04). No adverse events, including hyperkalemia or hypotension, were reported. Conclusions: Finerenone showed promise in reducing albuminuria and blood pressure among patients with nondiabetic chronic kidney disease, with no significant adverse effects reported. These findings suggest potential benefits for this patient population, warranting further investigation. Full article
(This article belongs to the Special Issue Pharmaceutical Treatments for Typical CKD Comorbidities)
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17 pages, 2375 KB  
Article
Extracellular Vesicles-Dependent Secretion Regulates Intracellular CYFIP2 Protein Homeostasis in Cortical Neurons
by Michael J. Culp, Breandan J. Rosolia, Cameron Keyser and Jingqi Yan
Biomedicines 2025, 13(10), 2518; https://doi.org/10.3390/biomedicines13102518 - 15 Oct 2025
Abstract
Background: Fragile X Syndrome (FXS) is the most common monogenic cause of autism spectrum disorders, and is characterized by the excessive immature excitatory synapses in cortical neurons, leading to excitatory/inhibitory imbalance and core autistic behaviors. This synaptic pathology has been attributed to [...] Read more.
Background: Fragile X Syndrome (FXS) is the most common monogenic cause of autism spectrum disorders, and is characterized by the excessive immature excitatory synapses in cortical neurons, leading to excitatory/inhibitory imbalance and core autistic behaviors. This synaptic pathology has been attributed to dysregulated levels of synaptic proteins, including CYFIP2: a key regulator of synaptic structure and plasticity. However, the mechanism underlying the increased CYFIP2 protein level in FXS neurons remains unclear. Neurons abundantly secrete extracellular vesicles (EVs) enriched with bioactive cargos (proteins and miRNAs). Objectives: the goal of this research is to identify whether EV-dependent secretion plays important roles in regulating the intracellular CYFIP2 protein level in WT and FXS neurons. Methods and Results: our proteomic analysis reveals that CYFIP2 protein is packaged in EVs released by mouse cortical neurons. Pharmacological and genetic blockades of neuronal EV release significantly elevated intracellular CYFIP2 levels by 78 ± 14% and 168 ± 39%, respectively. Glutamate-evoked EV release significantly reduced the CYFIP2 level by 24 ± 2%. Neurons from Fmr1 KO mice, an FXS model, secreted significantly less EVs (46 ± 5%) than the wild type, and showed significantly elevated CYFIP2 (by 155 ± 31%). Evoking EV release in FXS neurons significantly lowered the intracellular CYFIP2 (by 53 ± 6%). Conclusions: these findings identify an EV-secretion-dependent mechanism that controls neuronal CYFIP2 level, implicating EV-mediated export in the regulation of synaptic protein homeostasis, synaptic remodeling, and FXS-associated synaptic deficits. Full article
(This article belongs to the Special Issue Genetic Research on Neuropsychiatric Disorders and Complex Human Diseases)
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23 pages, 1123 KB  
Article
Omega-3 LCPUFAs (Long-Chain Polyunsaturated Fatty Acids) and Reading: The Mediating Role of Auditory Processing and the Interactions Among PUFAs
by Maria Luisa Lorusso, Francesca Borasio, Carlo Agostoni, Eva Marie-Louise Syren, Stefano Turolo, Mariagrazia Benassi, Roberto Bolzani, Antonio Salandi, Francesca Nicoli, Marilena Vecchi, Malida Franzoi, Federica Martinez, Daniela Traficante and Massimo Molteni
Biomedicines 2025, 13(10), 2517; https://doi.org/10.3390/biomedicines13102517 - 15 Oct 2025
Abstract
Background: The present study aimed to clarify the neurocognitive processes through which blood levels of omega-3 LCPUFAs affect reading and writing abilities. Methods: A total of 74 school-age children whose reading and writing skills varied from normal to largely below normal underwent [...] Read more.
Background: The present study aimed to clarify the neurocognitive processes through which blood levels of omega-3 LCPUFAs affect reading and writing abilities. Methods: A total of 74 school-age children whose reading and writing skills varied from normal to largely below normal underwent an assessment of reading and writing abilities, auditory and visual processing, phonological awareness, attention, and executive functions. Exploratory factor analysis extracted three neuropsychological factors whose roles as mediators between omega-3 LCPUFAs and reading/writing abilities were tested in GLM mediation models. The possible interactions with other PUFAs were further investigated. Results (on 73 participants): Omega-3 LCPUFA levels (EPA and DHA) correlated with reading and writing abilities and with the three extracted factors. Auditory–phonological processing skills were found to be significant mediators of the effect of PUFAs (especially EPA) on reading and writing abilities, whereas DHA and AA/ALA significantly moderated some of these effects. Conclusions: The link between omega-3 LCPUFAs and reading and writing abilities seems to be mediated mainly by the effects of LCPUFAs on auditory–phonological processing skills. These effects are especially linked to EPA, but they are modulated by DHA and AA/ALA levels. Hypotheses about possible molecular mechanisms at the basis of these effects are discussed. Full article
(This article belongs to the Special Issue From Molecules to Medicine: Deciphering Obesity and Lipid Metabolism for Translational Insights)
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33 pages, 3034 KB  
Systematic Review
Intraoperative Nerve Monitoring Parameters and Risk of Recurrent Laryngeal Nerve Injury in Thyroidectomy: A Systematic Review and Meta-Analysis
by Shlomo Merchavy, Kenan Kassem, Rifat Awawde, Uday Abd Elhadi and Alaa Safia
Biomedicines 2025, 13(10), 2516; https://doi.org/10.3390/biomedicines13102516 - 15 Oct 2025
Abstract
Background/Objectives: Recurrent laryngeal nerve injury (RLNI) is a major complication of thyroidectomy, affecting voice, airway protection, and quality of life. Intraoperative nerve monitoring (IONM) has been introduced to complement direct nerve visualization and reduce RLNI risk, but its efficacy remains controversial. This systematic [...] Read more.
Background/Objectives: Recurrent laryngeal nerve injury (RLNI) is a major complication of thyroidectomy, affecting voice, airway protection, and quality of life. Intraoperative nerve monitoring (IONM) has been introduced to complement direct nerve visualization and reduce RLNI risk, but its efficacy remains controversial. This systematic review and meta-analysis aimed to determine RLNI prevalence with IONM, compare rates with historical no-IONM cohorts, perform head-to-head comparisons, and assess the influence of IONM characteristics. Methods: PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar were searched for studies reporting RLNI rates in thyroidectomy with and without IONM. Pooled prevalence estimates were calculated for transient and permanent unilateral and bilateral RLNI in IONM studies and historical controls. Direct meta-analysis estimated pooled odds ratios (ORs) for RLNI risk reduction. Subgroup analyses examined IONM type, monitoring model, stimulation amplitude, voltage, and neuromuscular blockade use; meta-regression identified influential parameters. Results: A total of 103 studies involving 132,212 patients met the criteria. Unilateral transient RLNI was lower with IONM (4%, 95% CI: 4–5%) than in historical controls (5%, 95% CI: 4–6%), while unilateral permanent RLNI was 1% in both groups. Bilateral RLNI was rare. Direct comparison showed a 38% reduction in transient unilateral RLNI (OR: 0.62, 95% CI: 0.42–0.79) and a 51% reduction in permanent unilateral RLNI (OR: 0.49, 95% CI: 0.34–0.70) with IONM. Continuous IONM, lower stimulation amplitudes (≤2 mA), and avoidance of neuromuscular blockade were protective. Conclusions: IONM significantly reduces RLNI risk, particularly for unilateral injuries, with optimal protection achieved through continuous monitoring, low stimulation amplitudes, and avoidance of neuromuscular blockade. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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17 pages, 695 KB  
Review
Statins, Vitamin D, and Cardiovascular Health: A Comprehensive Review
by Dragos Cozma, Cristina Tudoran and Cristina Văcărescu
Biomedicines 2025, 13(10), 2515; https://doi.org/10.3390/biomedicines13102515 - 15 Oct 2025
Abstract
Statins are widely used lipid-lowering agents that significantly reduce cardiovascular morbidity and mortality by lowering LDL-cholesterol. Vitamin D, traditionally known for its skeletal role, is increasingly recognized for its cardiovascular relevance. This study aims to focus on the complex relationship between statins, vitamin [...] Read more.
Statins are widely used lipid-lowering agents that significantly reduce cardiovascular morbidity and mortality by lowering LDL-cholesterol. Vitamin D, traditionally known for its skeletal role, is increasingly recognized for its cardiovascular relevance. This study aims to focus on the complex relationship between statins, vitamin D, and their impact on cardiovascular outcomes. Both molecules intersect metabolically at 7-dehydrocholesterol, raising interest in their potential interactions. While theoretical concerns exist about statins impairing vitamin D synthesis, clinical studies suggest a neutral or modestly positive effect on circulating 25(OH)D levels. Statins may increase vitamin D levels by inhibiting its catabolism (via CYP3A4) and enhancing absorption. Observational data also suggest synergy between statins and vitamin D in reducing inflammation, oxidative stress, endothelial dysfunction, and atherogenesis. Though large trials showed no benefit of vitamin D supplementation in cardiovascular event reduction among vitamin D–replete individuals, select subgroups (those deficient or with statin-induced myalgia) may benefit from targeted supplementation. Optimizing vitamin D status could improve statin tolerability and adherence, especially in high-risk populations such as the elderly or those with metabolic syndrome. This review highlights the complex interplay between statins and vitamin D and supports a personalized approach to supplementation in statin-treated patients, aiming to enhance cardiovascular protection without overtreatment. Full article
(This article belongs to the Special Issue Connections Between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies—Second Edition)
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21 pages, 4803 KB  
Article
β-Caryophyllene as a Novel Modulator of the Renin–Angiotensin System: A Path to Reduce Inflammation and Restore Taste Function
by Sofía Cecilia López-Salido, Hugo Alejandro Espinoza-Gutiérrez, Mario Eduardo Flores-Soto, Alma Hortensia Martínez-Preciado and Juan Manuel Viveros-Paredes
Biomedicines 2025, 13(10), 2514; https://doi.org/10.3390/biomedicines13102514 - 15 Oct 2025
Abstract
Background/Objectives: Dysgeusia is a taste disorder commonly associated with chronic inflammation, reducing the quality of life, particularly in ageing populations or individuals with non-communicable chronic diseases. This study aimed to evaluate the effect of β-Caryophyllene, a natural sesquiterpene and agonist of the [...] Read more.
Background/Objectives: Dysgeusia is a taste disorder commonly associated with chronic inflammation, reducing the quality of life, particularly in ageing populations or individuals with non-communicable chronic diseases. This study aimed to evaluate the effect of β-Caryophyllene, a natural sesquiterpene and agonist of the cannabinoid receptor 2 (CB2), on dysgeusia through an analysis of inflammation, Renin–Angiotensin System (RAS) and taste perception. Methods: Male BALB/c mice were subjected to a dysgeusia model induced by molecular mimicry with lipopolysaccharide. Animals received intraperitoneal injections of lipopolysaccharide in a chronic–persistent regimen, starting at a dose of 35 μg/100 g body weight for 7 days until reaching a final concentration of 250 μg/100 g and a daily oral administration of β-Caryophyllene at a dose of 10 mg/kg. The effect of β-Caryophyllene on taste perception, inflammatory biomarkers, RAS key-elements, CB2 expression and physiological parameters was evaluated. Results: Data indicate that β-Caryophyllene attenuates systemic inflammation by decreasing IL-1β and IL-6 and increasing ACE2 enzymatic activity in lingual tissue. Also, it was shown that the sesquiterpene reduced taste cell apoptosis and improved sucrose preference, suggesting a feasible restoration of taste dysfunction. Conclusions: These findings demonstrate that β-Caryophyllene could be a potential candidate for treating dysgeusia due to its putative anti-inflammatory and angiotensinergic effects. Full article
(This article belongs to the Special Issue The Renin–Angiotensin System in Immune Regulation: Roles in Blood, Vessels, and Inflammation)
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39 pages, 3698 KB  
Review
From Steatosis to Immunosenescence: The Impact of Metabolic Dysfunction on Immune Aging in HIV and Non-HIV Populations
by Carlo Acierno, Maria Frontuto, Giulio Francesco De Stefano, Ana Erezanu, Andrea Limone, Simona Morella, Francesco Picaro, Donatella Palazzo and Michele Gilio
Biomedicines 2025, 13(10), 2513; https://doi.org/10.3390/biomedicines13102513 - 15 Oct 2025
Abstract
Immunosenescence, defined as the progressive decline of immune function with age, is increasingly recognized as a determinant of morbidity in people living with HIV (PLWH) and in individuals with metabolic dysfunction. The coexistence of chronic viral infection and systemic metabolic alterations—including metabolic dysfunction-associated [...] Read more.
Immunosenescence, defined as the progressive decline of immune function with age, is increasingly recognized as a determinant of morbidity in people living with HIV (PLWH) and in individuals with metabolic dysfunction. The coexistence of chronic viral infection and systemic metabolic alterations—including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus—creates a pro-inflammatory state (“metaflammation”) that accelerates immune aging. This narrative review synthesizes current clinical, translational, and experimental evidence on the cellular, molecular, and metabolic mechanisms underlying immunosenescence in HIV-positive and HIV-negative populations with metabolic dysfunction. Key converging pathways include chronic inflammation, mitochondrial dysfunction, microbial translocation, and altered immunometabolic signaling, leading to features such as CD8+CD28− T-cell expansion, reduced CD4/CD8 ratios, and impaired vaccine responses. Biomarkers such as iAge, IMM-AGE, and the triglyceride–glucose (TyG) index have emerged as promising tools to quantify immune aging beyond chronological measures. Understanding these interconnected mechanisms offers opportunities for targeted interventions—such as metabolic reprogramming, microbiota modulation, and geroscience-based strategies—aimed at preserving immune resilience and promoting healthy aging in high-risk populations. Full article
(This article belongs to the Collection Feature Papers in Obesity, Type 2 Diabetes and Metabolic Syndrome)
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27 pages, 1443 KB  
Review
Unveiling the Role of CCL3: A Driver of CIPN in Colon Cancer Patients?
by Irene Luzac, Cynthia Rosa Regalado and Mihály Balogh
Biomedicines 2025, 13(10), 2512; https://doi.org/10.3390/biomedicines13102512 - 15 Oct 2025
Abstract
Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer [...] Read more.
Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer progression but also to chemotherapy-induced side effects such as peripheral neuropathy. Chemokines, particularly CCL3, appear to be key players in this bidirectional communication. This literature review aims to critically examine the role of CCL3 in CRC and chemotherapy-induced peripheral neuropathy (CIPN), with a focus on identifying potential mechanistic overlaps. Specifically, we evaluate whether CCL3 may serve as a molecular link between cancer progression and the development of neuropathic pain. In CRC, CCL3 is frequently upregulated, promoting tumor proliferation, invasion, and immune remodeling through CCR5- and MAPK-dependent pathways. Elevated CCL3 expression correlates with advanced stage, nerve infiltration, and worse prognosis, while select studies suggest it may also enhance antitumor immunity via dendritic cell recruitment. In parallel, CCL3 is also upregulated in the nervous system during CIPN, where it contributes to chronic pain through activation of glial cells, sensitization of nociceptive pathways (e.g., TRPV1, P2X7), and desensitization of opioid receptors. Notably, MAPK signaling is a shared downstream pathway in both contexts, suggesting a potential mechanistic bridge between tumor biology and neurotoxicity. In conclusion, CCL3 emerges as a central molecule at the intersection of CRC and CIPN. Understanding its context-dependent roles may offer new opportunities for risk prediction, biomarker development, and therapeutic intervention—contributing to the broader goals of cancer neuroscience in improving both oncologic and neurologic outcomes. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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10 pages, 402 KB  
Article
The Role of Immature Granulocytes in Fibromyalgia: An Indicator of Subclinical Inflammation?
by Mehmet Serhat Topaloğlu, Medeni Arpa, Bayram Şen, Hacer Bilgin Topaloğlu and Osman Cüre
Biomedicines 2025, 13(10), 2511; https://doi.org/10.3390/biomedicines13102511 - 15 Oct 2025
Abstract
Background: Fibromyalgia (FM) is a chronic musculoskeletal disorder characterized by widespread body pain and various symptoms. Its etiology remains unclear to date. It has been associated with various pathogenic mechanisms, primarily inflammation. Immature granulocytes (IGs) have been proposed as a potential biomarker, playing [...] Read more.
Background: Fibromyalgia (FM) is a chronic musculoskeletal disorder characterized by widespread body pain and various symptoms. Its etiology remains unclear to date. It has been associated with various pathogenic mechanisms, primarily inflammation. Immature granulocytes (IGs) have been proposed as a potential biomarker, playing a role in both inflammatory responses and prognosis in numerous diseases. No other study has investigated the count of immature granulocytes (IG#) and percentage of immature granulocytes (IG%) in FM patients. The aim of this study is to investigate the IG# and IG% in FM patients and to evaluate the relationship between these parameters and disease parameters. Methods: This retrospective observational study included 95 patients diagnosed with FM and 63 healthy control subjects matched for body mass index and gender. Biochemical, hematological parameters, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and other inflammatory markers were recorded for both groups. Fibromyalgia Survey Diagnostic Criteria and Severity Scale (FSDC) and Fibromyalgia Impact Questionnaire (FIQ) scores were recorded for FM patients. Results: In FM patients, the IG% and IG# were significantly higher than in the healthy control group (p < 0.001, p: 0.006, respectively). There was no significant difference between the CRP and ESR values of the two groups. The platelet large cell count (PLCC) was significantly lower in the FM group (p < 0.032). Conclusions: IG levels can be used as a systemic early, sensitive, and low-cost marker in patients with FM. Based on our current knowledge, and considering the heterogeneous nature of FM, IG levels may serve as a meaningful tool in identifying subgroup elements reflecting an inflammatory phenotype. However, these findings require further validation through larger sample size, prospective studies, and advanced analyses including cytokine levels. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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11 pages, 292 KB  
Article
A Protein-Based Blood Test for Multi-Cancer Diagnostics
by Douglas Held, Steven Bolland, Robert Freese and Robert Puskas
Biomedicines 2025, 13(10), 2510; https://doi.org/10.3390/biomedicines13102510 - 15 Oct 2025
Abstract
Background/Objectives: Conventional cancer screening relies heavily on imaging and invasive procedures, leading to high false-positive rates and limited uptake, while leaving several high-mortality cancers without routine screening options. This study evaluated a protein-based multi-cancer early detection (MCED) test designed to detect five high-burden [...] Read more.
Background/Objectives: Conventional cancer screening relies heavily on imaging and invasive procedures, leading to high false-positive rates and limited uptake, while leaving several high-mortality cancers without routine screening options. This study evaluated a protein-based multi-cancer early detection (MCED) test designed to detect five high-burden cancers with high sensitivity, specificity, and tissue-of-origin (TOO) accuracy. Methods: Serum from 141 patients with confirmed breast, lung, colorectal, ovarian, or pancreatic cancer and 119 healthy controls was analyzed using a 16-parameter protein biomarker panel. The assay measured extracellular protein kinase A (xPKA) activity, additional kinase activities, and cancer-associated antibodies (IgG, IgM). A supervised, rule-based classification framework was developed for cancer detection and TOO assignment. Results: The MCED test achieved 100% sensitivity across all five cancer types and 97% overall specificity, with 98% TOO accuracy. Importantly, 100% of Stage I cancers were detected. Cancer specificities ranged from 96.6% (breast) to 100% (ovarian, pancreatic, and colorectal). Conclusions: This protein-based MCED approach demonstrates exceptional performance for multi-cancer detection and TOO identification, including robust early-stage detection, and may reduce the downstream diagnostic burden relative to the existing system. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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10 pages, 568 KB  
Article
Retained Lead Fragments in Superior Vena Cava and Early Post-Transplant Outcomes: A Single Center Preliminary Retrospective Study
by Federica Mazzone, Lorenzo Giovannico, Vincenzo Ezio Santobuono, Giuseppe Fischetti, Domenico Parigino, Luca Savino, Claudia Leo, Giuseppe Cristiano, Aldo Domenico Milano, Andrea Igoren Guaricci, Massimo Padalino, Marco Matteo Ciccone and Tomaso Bottio
Biomedicines 2025, 13(10), 2509; https://doi.org/10.3390/biomedicines13102509 - 15 Oct 2025
Abstract
Background/Objectives: Retained fragments of cardiovascular implantable electronic device (CIED) leads are frequently observed after orthotopic heart transplantation (OHT), but their clinical relevance remains unclear. Methods: We conducted a single-center, retrospective study of 179 adult patients who underwent OHT between January 2022 [...] Read more.
Background/Objectives: Retained fragments of cardiovascular implantable electronic device (CIED) leads are frequently observed after orthotopic heart transplantation (OHT), but their clinical relevance remains unclear. Methods: We conducted a single-center, retrospective study of 179 adult patients who underwent OHT between January 2022 and January 2025. Post-transplant imaging was used to identify retained lead fragments. Patients were grouped based on the presence or absence of retained leads. The primary endpoint was all-cause mortality at 30, 90, and 150 days post-transplant. Survival analysis was performed using Kaplan–Meier estimates and Cox proportional hazards modeling. Results: Among 112 patients with pre-transplant CIEDs, 18 (16%) had retained intravascular lead fragments. These patients had significantly lower survival at 30 days (66.7% vs. 94.7%), 90 days (61.1% vs. 90.3%), and 150 days (55.0% vs. 83.5%) compared to those without retained fragments (log-rank p = 0.002). The presence of retained leads was independently associated with increased mortality (HR: 3.71; 95% CI: 1.55–8.84; p = 0.003), even after adjusting for potential confounders. Conclusions: Retained CIED lead fragments are independently associated with higher early post-transplant mortality. These findings support the need for individualized intraoperative strategies to mitigate hardware-related risks in high-risk transplant candidates. Full article
(This article belongs to the Special Issue Advanced Research on Heart Failure and Heart Transplantation)
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18 pages, 3874 KB  
Article
BMP3 Deficiency Accelerates Cartilage-to-Bone Transition in Ectopic Bone
by Viktorija Rumenović, Natalia Ivanjko, Nataša Kovačić, Slobodan Vukičević and Igor Erjavec
Biomedicines 2025, 13(10), 2508; https://doi.org/10.3390/biomedicines13102508 - 15 Oct 2025
Abstract
Background: Ectopic bone formation models provide useful insights into bone tissue formation and remodeling processes. The use of a subcutaneous site emphasizes the focus on cytokine signaling and cell migration and proliferation while minimizing the effect of mechanical loading and direct interaction with [...] Read more.
Background: Ectopic bone formation models provide useful insights into bone tissue formation and remodeling processes. The use of a subcutaneous site emphasizes the focus on cytokine signaling and cell migration and proliferation while minimizing the effect of mechanical loading and direct interaction with surrounding stem cells. Methods: To study the effect of BMP3 on bone formation and remodeling, Bmp3-/- mice were subcutaneously implanted with an autologous blood coagulum device containing BMP6, and bone formation was examined at days 7 and 14 post-implantation. Bone marrow cell composition was assessed using FACS. Formation of ectopic bone was analyzed using micro-CT, immunohistochemistry, and RNAseq to obtain transcriptomic data. Results: Bone marrow from Bmp3-/- mice showed reduced lymphoid-lineage subsets, expanded myeloid lineage, and altered proportions of several osteochondroprogenitor subsets. A limited amount of newly formed bone tissue was seen in the implants after 7 days, while ectopic bone was more evident after 14 days, with significantly more bone in the Bmp3-/- mice compared to WT mice. Localization of Sox9 and Runx2 showed a more advanced stage of bone tissue remodeling in Bmp3-/- mice. Transcriptomic analysis showed upregulation of approximately 1700 genes on day 7 and 190 genes on day 14. Conclusions: These results suggest that BMP3 regulates the composition of bone and cartilage progenitor populations in bone marrow and consequently bone formation by arresting the remodeling of cartilage to bone tissue. The lack of BMP3 in ectopic bone accelerates the transition from the cartilaginous template to proper bone tissue. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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20 pages, 3275 KB  
Article
Machine Learning-Based Models for the Prediction of Postoperative Recurrence Risk in MVI-Negative HCC
by Chendong Wang, Qunzhe Ding, Mingjie Liu, Rundong Liu, Qiang Zhang, Bixiang Zhang and Jia Song
Biomedicines 2025, 13(10), 2507; https://doi.org/10.3390/biomedicines13102507 - 15 Oct 2025
Abstract
Background: Hepatocellular carcinoma (HCC) patients without microvascular invasion (MVI) face significant postoperative early recurrence (ER) risks, yet prognostic determinants remain understudied. Existing models often rely on linear assumptions. This study aimed to develop and validate an interpretable machine learning model using routine [...] Read more.
Background: Hepatocellular carcinoma (HCC) patients without microvascular invasion (MVI) face significant postoperative early recurrence (ER) risks, yet prognostic determinants remain understudied. Existing models often rely on linear assumptions. This study aimed to develop and validate an interpretable machine learning model using routine clinical parameters to predict early recurrence (ER) in MVI-negative HCC patients. Methods: We retrospectively analyzed 578 MVI-negative HCC patients undergoing radical resection. Seven machine learning (ML) algorithms were systematically benchmarked using clinical/laboratory/imaging features optimized via recursive feature elimination (RFE) and hyperparameter tuning. Model interpretability was achieved via SHapley Additive exPlanations (SHAP). Results: The CatBoost model demonstrated superior performance (AUC: 0.7957, Accuracy: 0.7290). SHAP analysis identified key predictors: tumor capsule absence, elevated HBV-DNA and CA125 levels, larger tumor diameter, and lower body weight significantly increased ER risk. Individualized SHAP force plots enhanced clinical interpretability. Conclusions: The CatBoost model exhibits robust predictive performance for ER in MVI-negative HCC, offering a clinically interpretable tool for personalized risk stratification and optimization of postoperative management strategies. Full article
(This article belongs to the Special Issue Advances in Hepatology)
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22 pages, 2281 KB  
Systematic Review
Incidence Rate and Determinants of Recurrent Cholesteatoma Following Surgical Management: A Systematic Review, Subgroup, and Meta-Regression Analysis
by Saqr Massoud, Raed Farhat, Uday Abd Elhadi, Rifat Awawde, Shlomo Merchavy and Alaa Safia
Biomedicines 2025, 13(10), 2506; https://doi.org/10.3390/biomedicines13102506 - 14 Oct 2025
Abstract
Background/Objectives: Cholesteatoma is a destructive middle ear pathology that can cause chronic infection, ossicular erosion, and hearing loss. While surgical excision is the standard treatment, recurrence remains a major clinical challenge, and comprehensive data on long-term outcomes are limited. This meta-analysis evaluated cholesteatoma [...] Read more.
Background/Objectives: Cholesteatoma is a destructive middle ear pathology that can cause chronic infection, ossicular erosion, and hearing loss. While surgical excision is the standard treatment, recurrence remains a major clinical challenge, and comprehensive data on long-term outcomes are limited. This meta-analysis evaluated cholesteatoma recurrence rates following surgery, identified clinical and surgical predictors of recurrence, and assessed trends across follow-up durations, techniques, and patient demographics. Methods: We searched PubMed, Scopus, Web of Science, CENTRAL, and Google Scholar for relevant studies (CRD42024550351). Studies reporting postoperative recurrence were included. Data on demographics, surgical approach, cholesteatoma type, and outcomes were extracted. Risk of bias was assessed using the Newcastle–Ottawa Scale. Pooled recurrence rates were calculated using random-effects models, and subgroup and meta-regression analyses were performed to identify predictors. Results: Eighty-four studies comprising 12,819 patients were included. The cholesteatoma recurrence rate showed geographic variability. Recurrence was higher in children (13%) than adults (10%), and in acquired (12%) versus congenital (7%) cholesteatoma. Advanced-stage disease, left-sided lesions, and revision surgeries increased recurrence risk. Canal wall down had lower recurrence (7%) than canal wall up techniques (16%). Adjuncts such as mastoid obliteration, ossicular reconstruction, and planned second-look surgeries reduced recurrence. Cumulative recurrence reached 39% at 15 years and 33% at 25 years. Meta-regression identified age, staged procedures, and second-look surgeries as independent predictors. Conclusions: Cholesteatoma recurrence is influenced by age, surgical approach, and disease severity. CWD procedures and comprehensive surgical planning reduce recurrence risk. Long-term follow-up and standardized outcome definitions are essential to improve monitoring and disease control. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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30 pages, 5265 KB  
Systematic Review
Effects of Whole-Body, Local, and Modality-Specific Vibration Therapy on Gait in Parkinson’s Disease: A Systematic Review and Meta-Analysis
by Ji-Woo Seok and Se-Ra Park
Biomedicines 2025, 13(10), 2505; https://doi.org/10.3390/biomedicines13102505 - 14 Oct 2025
Abstract
Background/Objectives: Gait dysfunction is a major contributor to disability and reduced quality of life in Parkinson’s disease (PD). Although pharmacological treatments and exercise-based rehabilitation programs provide partial improvement, residual gait dysfunction often persists. Given these limitations, there has been growing interest in non-pharmacological [...] Read more.
Background/Objectives: Gait dysfunction is a major contributor to disability and reduced quality of life in Parkinson’s disease (PD). Although pharmacological treatments and exercise-based rehabilitation programs provide partial improvement, residual gait dysfunction often persists. Given these limitations, there has been growing interest in non-pharmacological and non-invasive strategies such as vibration therapy (VT). However, previous systematic reviews and meta-analyses have yielded inconsistent findings, largely summarizing the presence or absence of treatment effects without clarifying the clinical or therapeutic conditions under which VT may be most effective. Therefore, this study aimed to systematically review and synthesize evidence on the efficacy of VT for improving gait in PD and to identify clinical and therapeutic factors influencing treatment outcomes. Methods: A systematic search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted with no restrictions on the search period, including studies published up to July 2025. Eligible studies included randomized and quasi-experimental clinical trials that evaluated the effects of VT on gait-related outcomes in patients with Parkinson’s disease. Data extraction followed the PRISMA 2020 guidelines, and the risk of bias was assessed using the Cochrane RoB 2 and ROBINS-I tools. Multilevel random-effects meta-analyses were conducted to estimate pooled effect sizes for gait outcomes, and meta-regression and subgroup analyses were performed based on disease stage, medication status, and vibration parameters. Results: A total of 14 studies (11 randomized and 3 non-randomized) were included. The pooled analysis showed that VT significantly improved gait performance in PD (Hedges’ g = 0.270, 95% CI: 0.115–0.424; 95% PI: −0.166–0.705). The sensitivity analysis restricted to randomized controlled trials yielded a comparable significant effect (g = 0.316, 95% CI: 0.004–0.628). Greater benefits were observed in patients with higher clinical severity, while the moderating effect of levodopa dosage was not significant. Optimal effects were identified with frequencies of 51–100 Hz, session durations ≤3 min, and 2–3 sessions per week. Improvements were evident in gait speed, cycle, and magnitude, whereas no consistent effects were observed for freezing of gait or gait variability. Conclusions: VT yields small but statistically significant improvements in fundamental gait parameters in Parkinson’s disease, particularly under optimized stimulation conditions and in individuals with greater disease severity. Although the pooled effect was modest and the certainty of evidence was rated as very low according to GRADE, these findings cautiously support the potential of vibration-based interventions as a supportive, non-pharmacological, and non-invasive adjunct within broader rehabilitation programs, rather than as a stand-alone treatment. Full article
(This article belongs to the Special Issue Challenges in the Diagnosis and Treatment of Parkinson’s Disease)
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6 pages, 232 KB  
Editorial
Mechanisms for Precision, Patient-Centered Therapy in Inflammatory Bowel Disease
by Dingpei Long
Biomedicines 2025, 13(10), 2504; https://doi.org/10.3390/biomedicines13102504 - 14 Oct 2025
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), arises from genetic susceptibility, environmental triggers, dysbiotic microbiota, and mucosal immune dysregulation [...] Full article
(This article belongs to the Special Issue Crohn's Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (2nd Edition))
8 pages, 721 KB  
Brief Report
Preclinical Tumor Growth Delay Is More Reliable from Imaging-Based Rather than Manual Caliper Volume Measurements
by Ifeanyichukwu Ogobuiro, Benjamin Spieler and Ivaylo B. Mihaylov
Biomedicines 2025, 13(10), 2503; https://doi.org/10.3390/biomedicines13102503 - 14 Oct 2025
Abstract
Background/Objectives: Tumor growth delay is frequently used in preclinical experiments evaluating oncologic interventions. While treatment response in humans is based on imaging criteria for obvious reasons, manual caliper measurement of subcutaneous tumors is standard in animal studies. In a murine tumor model treated [...] Read more.
Background/Objectives: Tumor growth delay is frequently used in preclinical experiments evaluating oncologic interventions. While treatment response in humans is based on imaging criteria for obvious reasons, manual caliper measurement of subcutaneous tumors is standard in animal studies. In a murine tumor model treated with immunotherapy (ImT) and radiotherapy (RT), the reliability of caliper measurements was tested by comparing normalized tumor growth delay (NTGD) rates derived from caliper- and image-based volumetrics. Methods: A 4T1 breast syngeneic murine model was used, in which thirty animals were inoculated in the right inguinal mammary fat pad and the right axilla. One RT fraction of 8 Gy was delivered to the right inguinal tumor on day 11 post-implant, and intraperitoneal ImT (PD-1 checkpoint inhibitor) injections were administered on days 11, 12, and 14. Each animal underwent three MRI scans (days 10, 17, and 20). Caliper measurements were also performed by two independent observers on the same days. The measurements were averaged and used to estimate ellipsoid tumor volumes. The acquired MRIs were used for image segmentation and volume estimation. Tumor volumes (days 17 and 20) were normalized against the baseline pre-treatment tumor volume (day 10). NTGD rates derived from hand- and image-based volumetrics were compared to assess the reliability of caliper vs. MRI estimation. Results: Caliper volumes between the two observers correlated at 0.799 (Pearson, p < 0.001). The averaged caliper volumes correlated with MRI volumes at 0.897 (Pearson, p < 0.001). Absolute volume differences between caliper and MRI increased with tumor growth. NTGD-derived rates showed no correlation, with only 15% of NTGD caliper rates falling within 10% of the MRI rates. Conclusions: NTGD rate based on caliper volumes is a suitable measure of treatment response in preclinical studies. In the experiment described herein, caliper-derived NTGD rates did not correlate with MRI ground truth. These findings suggest that more accurate tumor volumetrics, derived from stored and verifiable medical imaging sources, should be used in preclinical assessment of oncologic interventions instead of standard caliper estimates. Full article
(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer (2nd Edition))
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10 pages, 432 KB  
Article
Association Between Serum 25(OH)-Vitamin D and Heart Involvement in a Single-Centre Cohort of Children with Acute Rheumatic Fever During the Years 2004–2024
by Donato Rigante, Gabriella De Rosa, Angelica Bibiana Delogu, Giulia Pignataro, Claudia Di Pangrazio and Marcello Candelli
Biomedicines 2025, 13(10), 2502; https://doi.org/10.3390/biomedicines13102502 - 14 Oct 2025
Abstract
Background: An aberrant immune response against Streptococcus pyogenes combined with yet-unraveled genetic inference can induce acute rheumatic fever (ARF), but factors determining the specific development of rheumatic heart disease (RHD) are obscure. Objectives: To retrospectively assess general and laboratory data at [...] Read more.
Background: An aberrant immune response against Streptococcus pyogenes combined with yet-unraveled genetic inference can induce acute rheumatic fever (ARF), but factors determining the specific development of rheumatic heart disease (RHD) are obscure. Objectives: To retrospectively assess general and laboratory data at the onset of ARF in a single-centre cohort of children managed between 2004 and 2024, and to evaluate any potential relationship between serum vitamin D and the occurrence of RHD. Patients and Methods: Children with ARF diagnosed according to the revised Jones criteria, hospitalized and managed at the Department of Life Sciences and Public Health in our University, were considered; out of 90 eligible patients with post-streptococcal illness, 11 were not considered because they were diagnosed with post-streptococcal arthritis, while 1 was excluded due to incomplete inpatient data. A total final number of 78 consecutive children with ARF (39 males and 39 females) with a mean age of 10.6 ± 2.7 years was assessed via retrospective evaluation of medical records. Their demographic, clinical, and laboratory variables at disease onset, including C-reactive protein, anti-streptolysin-O titer, and 25-hydroxyvitamin D [25(OH)-vitamin D], were analyzed. Results: Sixty-six children (84.6% of the whole cohort) were found to have echocardiographic evidence of RHD. By dividing patients based on the presence of carditis, at the univariate analysis, we observed serum 25(OH)-vitamin D levels significantly lower in patients with cardiac involvement compared to those without (18 ± 6 versus 38 ± 8 ng/mL, p < 0.001). In addition, the proportion of patients with normal serum vitamin D levels was significantly higher among those without cardiac involvement (92%, p < 0.001). To account for any potential confounding factors, we performed a multivariate analysis using logistic regression, adjusted for sex and age, finding that 25(OH)-vitamin D levels lower than 30 ng/mL were the only variable associated with RHD (OR 27.752; 95% CI: 2.885–266.996). No relationship between vitamin D and the month of the year at diagnosis of ARF and RHD was found. Conclusions: Hypovitaminosis D was identified as a factor potentially associated with RHD occurrence in a single-centre cohort of children with ARF evaluated over two decades. This result may suggest that vitamin D deficiency contributes to the occurrence of carditis in ARF. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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1 pages, 140 KB  
Correction
Correction: Zhang et al. An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer. Biomedicines 2025, 13, 311
by Yuke Zhang, Li Ding, Zhijin Zhang, Liliang Shen, Yadong Guo, Wentao Zhang, Yang Yu, Zhuoran Gu, Ji Liu, Aimaitiaji Kadier, Jiang Geng, Shiyu Mao and Xudong Yao
Biomedicines 2025, 13(10), 2501; https://doi.org/10.3390/biomedicines13102501 - 14 Oct 2025
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Abstract
References [...] Full article
(This article belongs to the Section Cancer Biology and Oncology)
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